JP6968809B2 - Methods for Synthesizing Iodine-or Astatoarene Using Diaryl Iodonium Salts - Google Patents

Description

The present invention relates to a method for synthesizing iodo- or astathalene, which comprises reacting a diaryliodonium compound with an iodide or an astatate salt, respectively. The present invention also relates to the iodine-or astathalene and diaryliodonium compounds themselves. The present invention also relates to a method for synthesizing an iodine- or astato-labeled biomolecule and / or a vector using the iodine-or astatoarene.

Aryliodonium salts have been increasingly subjected to arylation of nucleophiles in the last decade due to their low toxicity, high regioselectivity achieved, and the mild reaction conditions required compared to conventional methods. It's becoming more common. Halogen has been investigated in detail for more than 50 years on the nucleophilic aromatic substitution of aryliodonium salts among the first nucleophiles. Nevertheless, it is only recently that applications for halogenation of these precursors have been developed ^{, especially in radiochemistry for radiation labeling of allenes with β +} -emitter fluorine-18 for positron emission tomography (PET). That is.

^In contrast to 18F, other radioactive halogens have received limited attention for their reaction with iodonium salts. For example, there are no reports of reactivity with radioactive bromides, iodides and astatates.

Many of the radioactive iodine-labeled and astatine-labeled compounds of interest in nuclear medicine are aromatic derivatives. This is because non-aromatic compounds often exhibit poor stability due to weak CI and C-At bonds. These aromatic compounds are generally obtained by conventional methods, such as nucleophilic substitution by halogen exchange, electrophilic substitution by halo demetallization, eg, conventional astato destannylation method, or direct substitution.

However, these reactions often raise concerns about low radiochemical yield (RCY), low specific activity, or toxicity of precursors and by-products when considered for human use. It is related.

Moreover, in certain cases of astatine labeling of aromatic compounds, electrophilic substitution of arylstannan is often the preferred method. This is because high yields are generally obtained under smooth conditions. However, for astatines that can be present in multiple oxidation states (-I, + I, + III, + V and + VII), obtaining pure At (+ I) at ultra-trace concentrations is difficult to control and At (+ I). ) And At (+III) species mixtures are difficult to avoid. In addition, the + I oxidation state has been shown to be unstable over time due to the radiation produced by the attenuation of astatine, which is exposed to the solution and results in a change in its oxidation state.

Therefore, there is a need to provide new methods for synthesizing iodine-or asta-arene, in particular radioactive iodine-or asta-arene. There is also a need to provide biomolecules and / or vectors that are radiolabeled with radioactive isotopes of iodine or astatine.

One object of the present invention is, among other things, to provide a method for synthesizing iodine-or astaarene in high and consistent yields.

One object of the present invention is, in particular, to provide a method for synthesizing iodine- or astathalene that is easy to carry out using an efficient, fast and low cost purification step.

Another object of the present invention is to synthesize iodo- or astathalene, which is less toxic than the iodine-or astato destannylation method, in particular avoiding the use of intermediate compounds containing tin and resulting in toxic by-products. Is to provide a method.

Another particular object of the present invention is to provide a method for synthesizing astathalene with the use of (-I) astatine in an oxidized state.

Also, one object of the present invention is to provide biomolecules and vectors that are radiolabeled using the iodine-or asta-arene.

Therefore, the present invention relates to a method for synthesizing iodo- or astathalene, which comprises reacting a diaryliodonium compound with an iodide or an astatate salt, respectively.

Surprisingly, we have shown that iodo- or astatalane compounds are reacted with iodide (-I) or astatates (-I) salts by reacting diaryliodonium compounds with astatates (-I), especially with high efficiency. It was found that it can be obtained by the reaction with −I). The reaction of the diallyl iodonium compound with the iodide or astatinate salt yields good yields of iodo-or astatoarene and is less toxic than the halo demetallization method, especially the iodo destannylation and astatine destannylization methods. Less toxic.

The present inventors have also found a technique for purifying an iodine- or astoarene compound. For example, HPLC (High Performance Liquid Chromatography) is typically used to separate iodine-or astatoarene from reagents and by-products prior to coupling with biomolecules. Performing HPLC is time consuming and results in a decrease in radiochemical yield (especially for ²¹¹ At, the half-life is about 7.214 hours). When the amount of astatine-labeled species contained is extremely low, such HPLC purification generally results in significant loss due to adsorption within the chromatography system (up to 80% of the astatine-labeled product of interest). Is also brought. Extraction of iodine-or astathalene with a solvent such as diethyl ether found by the present inventors is easier, faster and lower cost as compared with HPLC. Therefore, the refining process is improved and adapted to the industrial scale.

Even more strikingly, we have found that astatates unexpectedly exhibit higher reactivity than iodides in this context. This is because while the chemical behavior of astatine is often similar compared to iodide, the chemical behavior of the higher oxidation state of astatine is not well understood and tends to be observed for other halogens. It is surprising because it can be significantly different from.

The higher nucleophilic activation of the astatate anion alone is not sufficient to explain the sharp increase in reactivity obtained by the astatate as compared to the iodide in the context of the present invention. To explain this difference in reactivity, without being bound by theory, the reaction intermediate iodide iodide is a dimer or higher-order cluster morphology that requires more energy to dissociate. May be stabilized by. On the other hand, iodonium astatates more easily form the monomeric form by the formation of contact ion pairs desirable for the larger polarizability of the heaviest halides.

Accordingly, the methods according to the invention provide iodine-or astato-alene compounds, and above all, radioactive iodine-or radioactive astato-alene compounds that may be useful in nuclear medicine. In particular, the radioactive iodine-or radioactive astoarene compound according to the present invention can be conjugated to a biomolecule and / or a vector, and thus can be used for tumor treatment and / or localization.

Definitions The term _"(C 1 ~C ₆₎ alkyl" has from 1 to 6 carbon atoms in the chain can be straight-chain or branched-chain, means a saturated aliphatic hydrocarbon group .. "Branched chain" means that one or a lower alkyl group, such as methyl, ethyl or propyl, is attached to a straight chain alkyl chain. "Lower alkyl" means 1 to 4 carbon atoms in a chain, which can be straight or branched. Preferred alkyl groups are methyl, ethyl, propyl and isopropyl.

"(C _{2 to} C ₆ ) alkenyl" is an unsaturated alkyl containing at least one double bond between two carbon atoms and containing 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Means.

"(C _{2 to} C ₆ ) alkynyl" is an unsaturated alkyl containing at least one triple bond between two carbon atoms and containing 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. means.

The term "(C _{6 to} C ₁₀ ) aryl" is an aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring system in which any substituent ring atom is substituted with a substituent. Refers to a ring system that can be present. Examples of aryl moieties include, but are not limited to, phenyl and naphthyl, preferably phenyl.

The term "heteroaryl" is a 5- to 10-membered aromatic monocyclic or bicyclic group containing 1 to 4 heteroatoms selected from O, S or N, preferably S. , Refers to a group in which any substitutable ring atom can be substituted with a substituent. Examples of heteroaryl moieties include, but are limited to, thiophene or tetradine, such as 4-methyl- [1,2,4,5] -tetrazine or 3-methyl- [1,2,4,5] -tetrazine. Not done.

The term "halogen" (or "Hal") refers to the Group 17 atom (halogen) of the Periodic Table and includes fluorine, chlorine, bromine, iodine and astatine atoms, preferably chlorine, bromine, iodine and astatine atoms. .. The term "heavy halogen" refers to iodine and astatine atoms.

［式中、Ｒは、以下で定義されるＡｒ_１又はＡｒ_２である］
を有する化合物を指すことができる。 The term "cyclooctynyl" is used in the following formula (i).

[In the formula, R is Ar ₁ or Ar ₂ as defined below]
Can refer to a compound having.

［式中、Ｒは、以下で定義されるＡｒ_１又はＡｒ_２である］
を有する化合物を指すことができる。 The term "norbornenyl" is used in the following formula (ii).

[In the formula, R is Ar ₁ or Ar ₂ as defined below]
Can refer to a compound having.

［式中、Ｒは、Ａｒ_１又はＡｒ_２であり、Ｒ’は、Ｈ又は（Ｃ_１〜Ｃ_６）アルキルである］
を有する化合物を指すことができる。 The term "cyclopropenyl" is used in the following formula (iii).

[In the formula, R is Ar ₁ or Ar ₂ , and R'is H or (C _{1 to C 6} ) alkyl].
Can refer to a compound having.

［式中、Ｒは、Ａｒ_１又はＡｒ_２である］
を有する化合物を指すことができる。 The term "bicyclononinyl" is derived from the following formula (iv).

[In the formula, R is Ar ₁ or Ar ₂ ]
Can refer to a compound having.

［式中、Ｒは、Ａｒ_１又はＡｒ_２である］
のうちの一方を有する化合物を指すことができる。 The term "trans-cyclooctenyl" is used in the following formula (v) or (vi).

[In the formula, R is Ar ₁ or Ar ₂ ]
It can refer to a compound having one of the two.

The term "vector" refers to a molecule that is recognizable as a biological target tissue (depending on the pathology treated or detected).

Also, the term "vector" refers to organic compounds that bind to cells or organic compounds that are transported by transporters expressed by cells (including, but not limited to, glucose, amino acids, biogenic amines), peptide binding. It may also refer to sex-specific receptors (including, but not limited to, somatostatin, cholecystokinin, neurotensin receptors, substance P), haptens and drugs.

The term "vector" can also refer to nanocarrier compounds that can recognize target cells, such as nanocapsules, liposomes, dendrimers or carbon nanotubes. These nanocarriers can optionally bind to tumor-specific ligands.

A "biomolecule" is an antibody or fragment thereof or any antibody construct (eg, minibody, deerbody, etc. obtained by antibody engineering) and a recombinant protein or synthetic peptide selected to bind to a target cell (eg, affibody or). It is understood that it includes, but is not limited to, affitin.

Since the expression "functional group capable of binding to a vector and / or a biomolecule" is reactive with a chemical functional group of a vector and / or a biomolecule, the vector and / or the biomolecule and synton (according to the present invention). It refers to a chemical group that allows the formation of a stable chemical bond with iodo-or astatoarene, preferably one represented by formula (I) or (I-1)).

［式中、
Ａｒ_１及びＡｒ_２は、それぞれ独立して、（Ｃ_６〜Ｃ_１０）アリール及びヘテロアリール基から選択され、前記アリール及びヘテロアリール基は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、場合により置換されているヘテロアリール、ハロゲン、ＮＯ_２、ＣＮ、Ｎ_３、ＣＦ_３、−ＯＲａ、−ＣＯＯＲｂ、−Ｃ（Ｏ）Ｒａ、−Ｎ＝Ｃ＝Ｏ、−Ｎ＝Ｃ＝Ｓ、−Ｎ（Ｒａ）ＣＯＯＲｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｃ（Ｏ）Ｏ−Ｒｂ及びマレイミジルから選択される１つ又は複数の置換基により置換されており、
前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−Ｏ−（Ｃ_１〜Ｃ_６）アルキル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルケニルから選択される１つ又は複数の置換基により場合により置換されており、
Ｒａは、Ｈ又は（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒｂは、Ｈ、（Ｃ_１〜Ｃ_６）アルキル並びにベクター及び／又は生体分子に結合可能な官能基からなる群より選択され、
Ｙは、一価のアニオンであり、特に、ＣＦ_３ＣＯＯ、ＴｓＯ、ＭｓＯ（メシラート）、ＮｓＯ（ノシラート）、ＴｆＯ、ＮＯ_３、Ｂｒ、Ｃｌ、ＳＯ_４及びＢＦ_４から選択される］
で示されるものである、方法に関する。 Method for synthesizing iodine-or astatoarene Reaction of a diaryliodonium compound represented by the formula (II) or (II-1) with an iodide or an asstatide salt A method for synthesizing iodide-or astatoarene, which comprises reacting with, respectively, wherein the diallyl iodidenium compound is of formula (II) :.

[During the ceremony,
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl, (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb , - (C 1 ~C 6) alkylene -N (Ra) -C (O) -Rb, - (C 1 ~C 6) alkylene -N (Ra) -C (O )-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-C (O) O-Rb and It has been substituted with one or more substituents selected from maleimidyl and has been substituted.
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl and -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from alkenyl.
Ra is H or (C _1- C ₆ ) alkyl and is
Rb is, _H, is selected from the group consisting of _(C 1 _{~C 6)} alkyl and vectors and / or functional group capable of bonding to a biomolecule,
Y is a monovalent anion and is particularly selected from CF ₃ COO, TsO, MsO (mesylate), NsO (nosylate), TfO, NO ₃ , Br, Cl, SO ₄ and BF ₄ ].
With respect to the method, which is indicated by.

［式中、
Ａｒ_１及びＡｒ_２は、それぞれ独立して、（Ｃ_６〜Ｃ_１０）アリール及びヘテロアリール基から選択され、前記アリール及びヘテロアリール基は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、場合により置換されているヘテロアリール、ハロゲン、ＮＯ_２、ＣＮ、Ｎ_３、ＣＦ_３、−ＯＲａ、−ＣＯＯＲｂ、−Ｃ（Ｏ）Ｒ_ａ、−Ｎ＝Ｃ＝Ｏ、−Ｎ＝Ｃ＝Ｓ、−Ｎ（Ｒａ）ＣＯＯＲｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｃ（Ｏ）Ｏ−Ｒｂ及びマレイミジルから選択される１つ又は複数の置換基により置換されており、
前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−Ｏ−（Ｃ_１〜Ｃ_６）アルキル、−Ｏ−（Ｃ_１〜Ｃ_６）アルケニル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルキレン−（Ｃ_６〜Ｃ_１０）アリールから選択される１つ又は複数の置換基により場合により置換されており、
Ｒａは、Ｈ又は（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒｂは、Ｈ、（Ｃ_１〜Ｃ_６）アルキル並びにベクター及び／又は生体分子に結合可能な官能基からなる群より選択され、
Ｙは、一価のアニオンであり、特に、ＣＦ_３ＣＯＯ、ＴｓＯ、ＭｓＯ、ＮｓＯ、ＴｆＯ、ＮＯ_３、Ｂｒ、Ｃｌ、ＳＯ_４及びＢＦ_４から選択される］
で示されるものである、方法に関する。 The present invention also comprises reacting a diaryliodonium compound with an iodide or an astatine salt, respectively, to synthesize iodo- or astathalene, wherein the diaryliodonium compound is of formula (II) :.

[During the ceremony,
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl and (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) R _a , -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C ( O)-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-C (O) O-Rb And is substituted with one or more substituents selected from maleimidyl and
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl, and -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from alkenyl and -O- (C _1- C ₆ ) alkylene- (C _6- C _{10) aryl.}
Ra is H or (C _1- C ₆ ) alkyl and is
Rb is, _H, is selected from the group consisting of _(C 1 _{~C 6)} alkyl and vectors and / or functional group capable of bonding to a biomolecule,
Y is a monovalent anion and is particularly selected from CF ₃ COO, TsO, MsO, NsO, TfO, NO ₃ , Br, Cl, SO ₄ and BF ₄ ].
With respect to the method, which is indicated by.

で示されるものであり、下記のとおりである：
Ａｒ_１及びＡｒ_２は、それぞれ独立して、（Ｃ_６〜Ｃ_１０）アリール及びヘテロアリール基から選択され、前記アリール及びヘテロアリール基は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、場合により置換されているヘテロアリール、ハロゲン、ＮＯ_２、ＣＮ、Ｎ_３、ＣＦ_３、−ＯＲａ、−ＣＯＯＲｂ、−Ｃ（Ｏ）Ｒａ、−Ｎ＝Ｃ＝Ｏ、−Ｎ＝Ｃ＝Ｓ、−Ｎ（Ｒａ）ＣＯＯＲｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｃ（Ｏ）Ｏ−Ｒｂ及びマレイミジルから選択される１つ又は複数の置換基により置換されており、
前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−Ｏ−（Ｃ_１〜Ｃ_６）アルキル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルケニルから選択される１つ又は複数の置換基により場合により置換されており、
Ｒａは、Ｈ又は（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒｂは、Ｈ、（Ｃ_１〜Ｃ_６）アルキル、スクシンイミジル、Ｎ−ヒドロキシスクシンイミジル、スルホスクシンイミジル、マレイミジル、ビオチニル、シクロオクチニル、ノルボルネニル、シクロプロペニル、ビシクロノニニル及びtrans−シクロオクテニルからなる群より選択され、
Ｙは、一価のアニオンであり、特に、ＣＦ_３ＣＯＯ、ＴｓＯ、ＭｓＯ、ＮｓＯ、ＴｆＯ、ＮＯ_３、Ｂｒ、Ｃｌ、ＳＯ_４及びＢＦ_４から選択される。 In one embodiment, in the reactions referred to above, the diallyl iodonium compound is of formula (II) :.

It is indicated by and is as follows:
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl, (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb , - (C 1 ~C 6) alkylene -N (Ra) -C (O) -Rb, - (C 1 ~C 6) alkylene -N (Ra) -C (O )-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-C (O) O-Rb and It has been substituted with one or more substituents selected from maleimidyl and has been substituted.
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl and -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from alkenyl.
Ra is H or (C _1- C ₆ ) alkyl and is
Rb consists of H, (C _1- C ₆ ) alkyl, succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, cyclooctynyl, norbornenyl, cyclopropenyl, bicyclononinyl and trans-cyclooctenyl. Selected from the group,
Y is a monovalent anion and is particularly selected from CF ₃ COO, TsO, MsO, NsO, TfO, NO ₃ , Br, Cl, SO ₄ and BF ₄ .

で示されるものであり、下記のとおりである：
Ａｒ_１及びＡｒ_２は、それぞれ独立して、（Ｃ_６〜Ｃ_１０）アリール及びヘテロアリール基から選択され、前記アリール及びヘテロアリール基は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、場合により置換されているヘテロアリール、ハロゲン、ＮＯ_２、ＣＮ、Ｎ_３、ＣＦ_３、−ＯＲａ、−ＣＯＯＲｂ、−Ｃ（Ｏ）Ｒａ、−Ｎ＝Ｃ＝Ｏ、−Ｎ＝Ｃ＝Ｓ、−Ｎ（Ｒａ）ＣＯＯＲｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｃ（Ｏ）Ｏ−Ｒｂ及びマレイミジルから選択される１つ又は複数の置換基により置換されており、
前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−Ｏ−（Ｃ_１〜Ｃ_６）アルキル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルケニル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルキレン−（Ｃ_６〜Ｃ_１０）アリールから選択される１つ又は複数の置換基により場合により置換されており、
Ｒａは、Ｈ又は（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒｂは、Ｈ、（Ｃ_１〜Ｃ_６）アルキル、スクシンイミジル、Ｎ−ヒドロキシスクシンイミジル、スルホスクシンイミジル、マレイミジル、ビオチニル、シクロオクチニル、ノルボルネニル、シクロプロペニル、ビシクロノニニル及びtrans−シクロオクテニルからなる群より選択され、
Ｙは、一価のアニオンであり、特に、ＣＦ_３ＣＯＯ、ＴｓＯ、ＭｓＯ、ＮｓＯ、ＴｆＯ、ＮＯ_３、Ｂｒ、Ｃｌ、ＳＯ_４及びＢＦ_４から選択される。 In one embodiment, in the reactions referred to above, the diallyl iodonium compound is of formula (II) :.

It is indicated by and is as follows:
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl, (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb , - (C 1 ~C 6) alkylene -N (Ra) -C (O) -Rb, - (C 1 ~C 6) alkylene -N (Ra) -C (O )-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-C (O) O-Rb and It has been substituted with one or more substituents selected from maleimidyl and has been substituted.
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl and -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from alkenyl and -O- (C _1- C ₆ ) alkylene- (C _6- C _{10) aryl.}
Ra is H or (C _1- C ₆ ) alkyl and is
Rb consists of H, (C _1- C ₆ ) alkyl, succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, cyclooctynyl, norbornenyl, cyclopropenyl, bicyclononinyl and trans-cyclooctenyl. Selected from the group,
Y is a monovalent anion and is particularly selected from CF ₃ COO, TsO, MsO, NsO, TfO, NO ₃ , Br, Cl, SO ₄ and BF ₄ .

In one embodiment, Ra is H or _(C 1 _{~C 4)} alkyl. In another embodiment Ra is H, methyl, ethyl, propyl or isopropyl. Preferably Ra is H, methyl or isopropyl.

からなる群より選択される。 In one embodiment, _{Rb, H, (C 1 ~C 6} ) alkyl, succinimidyl, N- hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl and:

Selected from the group consisting of.

In another embodiment, _{Rb, H, (C 1 ~C 4} ) alkyl, succinimidyl, is selected from the group consisting of N- hydroxysuccinimidyl and maleimidyl, especially, Rb is a succinimidyl or maleimidyl.

In one embodiment, when Ar ₁ and / or Ar ₂ are substituted with heteroaryl, the heteroaryl is optionally _{substituted more than once with (C 1-} C ₆ ) alkyl, preferably methyl. ..

In one embodiment, Ar ₁ and Ar ₂ are not identical (ie, not symmetrical).

In one embodiment, Ar ₁ and Ar ₂ each independently consist of (5-6) -membered heteroaryls containing 1 to 4 heteroatoms selected from phenyl and O, S or N. The phenyl and (5-6) member heteroaryls are _{selected from 1 to 4 selected from (C 1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, O, S or N. 5-membered heteroaryl containing a heteroatom, halogen, NO ₂ , CN, N ₃ , CF ₃ , ORa, COORb, C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C ₁₎ ~ C ₆ ) alkylene-Rb, (C ₁ ~ C ₆ ) alkylene-N (Ra) -C (O)-(C ₁ ~ C ₆ ) alkylene-C (O) O-Rb and maleimidyl 1 Substituted by one or more substituents,
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , O-CH _2- O- (C _{1 to} C ₆ ) alkyl and -O- (C _{1 to} C ₆ ) alkenyl. It is optionally substituted with one or more substituents selected from, and Ra and Rb are as defined above.

In one embodiment, Ar ₁ and Ar ₂ each independently consist of (5-6) -membered heteroaryls containing 1 to 4 heteroatoms selected from phenyl and O, S or N. The phenyl and (5-6) member heteroaryls are _{selected from 1 to 4 selected from (C 1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, O, S or N. 6-membered heteroaryl containing a heteroatom, halogen, NO ₂ , CN, N ₃ , CF ₃ , ORa, COORb, C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C ₁₎ ~ C ₆ ) alkylene-Rb, (C ₁ ~ C ₆ ) alkylene-N (Ra) -C (O)-(C ₁ ~ C ₆ ) alkylene-C (O) O-Rb and maleimidyl 1 Substituted by one or more substituents,
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , O-CH _2- O- (C _{1 to} C ₆ ) alkyl, and -O- (C _{1 to} C ₆ ) alkenyl. And -O- (C _{1 to} C ₆ ) alkylene- (C _{6 to} C ₁₀ ) optionally substituted with one or more substituents selected from aryl, Ra and Rb as defined above. Is.

In another embodiment, Ar ₁ and Ar ₂ are independently phenyl or thiophene, which are methyl, (C ₂ ) alkynyl, Br, Cl, I, At, NO ₂ , CN. , N ₃ , OCH ₃ , -O-isopropyl, -C (O) O-succinimidyl, -C (O) O-CH _{2 -CH 3,} and substituted with one or more substituents selected from maleimidyl. The methyl group is optionally substituted with one or more substituents selected from _{N 3} , OH, OCH ₃ , CF ₃ and -O-CH ₂ -CH = CH _2.

から選択される１つ又は複数の置換基により置換されており、前記メチル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−ＣＨ＝ＣＨ_２及び

から選択される１つ又は複数の置換基により場合により置換されている。 In another embodiment, Ar ₁ and Ar ₂ are independently phenyl or thiophene, which are methyl, (C ₂ ) alkynyl, Br, Cl, I, At, NO ₂ , CN. , N ₃ , OCH ₃ , -O-isopropyl, -C (O) O-succinimidyl, -C (O) O-CH _{2 -CH 3} , maleimidyl, optionally substituted tetrazine and

Substituent with one or more substituents selected from, said methyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH ₂ -CH = CH ₂ and

It is optionally substituted with one or more substituents selected from.

In one embodiment, the aryl and heteroaryl groups of _{Ar 1} and Ar _{2 are preferably 1 to 4 selected from (C 1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, O, S or N. contain pieces of _{heteroatom, (C} 1 _{~C 6) 6-membered} heteroaryl substituted by alkyl, _{halogen, NO 2, CN, N 3} , CF 3, ORa, COORb, C (O) Ra and It has been substituted once or twice with a substituent independently selected from the group consisting of maleimidyl.
The (C _1- C ₆ ) alkyl groups are optionally substituted with one or more substituents selected from _{N 3} , OH, OCH ₃ , CF ₃ and -O-CH ₂ -CH = CH _2. Ra and Rb are as defined above.

In one embodiment, Ar ₁ and Ar ₂ are independently substituted with ORa, (C _{1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, N ₃ and C (O) O-succinimidyl, respectively. and which phenyl or thiophene group, wherein _(C 1 ~C ₆₎ alkyl group is optionally substituted by N _3, Ra is as defined above.

In one embodiment, Ar ₁ and Ar ₂ are _{phenyls that have been substituted with CH 3} and / or OCH ₃ 1 to 5 times, preferably 3 times.

［式中、
Ｒ_１は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、場合により置換されているヘテロアリール、ハロゲン、ＮＯ_２、ＣＮ、Ｎ_３、ＣＦ_３、−ＯＲａ、−ＣＯＯＲｂ、−Ｃ（Ｏ）Ｒａ、−Ｎ＝Ｃ＝Ｏ、−Ｎ＝Ｃ＝Ｓ、−Ｎ（Ｒａ）ＣＯＯＲｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｃ（Ｏ）Ｏ−Ｒｂ及びマレイミジルからなる群より選択され、
前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３及び−Ｏ−ＣＨ_２−ＣＨ＝ＣＨ_２から選択される１つ又は複数の置換基により場合により置換されており、
Ｒａ及びＲｂは、上記定義されたとおりである］
で示されるものである。 In one embodiment, the diallyl iodonium compound is of formula (II-1) :.

[During the ceremony,
R ₁ is (C _{1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb, -(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Selected from the group consisting of (C _1- C ₆ ) alkylene-C (O) O-Rb and maleemidyl.
The (C _1- C ₆ ) alkyl groups are optionally substituted with one or more substituents selected from _{N 3} , OH, OCH ₃ , CF ₃ and -O-CH ₂ -CH = CH _2. Ori,
Ra and Rb are as defined above]
It is indicated by.

In one embodiment, R ₁ is methyl, (C ₂ ) alkynyl, halogen, NO ₂ , CN, N ₃ , OCH ₃ , O-isopropyl, C (O) O-succinimidyl, C (O) O-CH _2. Selected from the group consisting of -CH ₃ , C (O) -N-hydroxysuccinimidyl and maleimidil.
The methyl group is optionally substituted with one or more substituents selected from _{N 3} , OH, OCH ₃ , CF ₃ and —O—CH ₂ −CH = CH _2.

In one embodiment, R ₁ is selected from the group consisting of ORa, (C _{1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, N ₃ and C (O) O-succinimidyl, as described above (C _1). -C ₆₎ alkyl group is optionally substituted by N _3, Ra is as defined above.

［式中、
Ｒｙ及びＲｚは、それぞれ独立して、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂからなる群より選択され、前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−ＣＨ＝ＣＨ_２及び

から選択される１つ又は複数の置換基により場合により置換されており、
Ｒａは、上記定義されたとおりである］
で示されるものである。 In one embodiment, the diallyl iodonium compound is of formula (II-2) :.

[During the ceremony,
Ry and Rz are independently (C _{1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb, respectively. -(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) selected from the group consisting of alkylene-Rb, the (C _{1 to} C ₆ ) alkyl group is N. ₃ , OH, OCH ₃ , CF ₃ , -O-CH ₂ -CH = CH ₂ and

Substituentally substituted with one or more substituents selected from
Ra is as defined above]
It is indicated by.

In one embodiment, Y ⁻ is TsO ⁻ or TfO ⁻ . In another ^{embodiment, Y} - ^is, TsO ^-, TfO - or BF4 @ ^- is.

から選択される。 In one embodiment, in the reaction defined above, the diaryliodonium compound represented by the formula (II) is the following compound:

Is selected from.

In one embodiment of the reaction defined above, iodo-or astaarene is the formula (I) :.
Ar-X (I)
[During the ceremony,
X is I or At,
Ar is Ar ₁ or Ar ₂ as defined above]
It is indicated by.

In one embodiment, X is radioactive. In one embodiment, X is selected from the group consisting of ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I and ^{211 At.} Preferably X is ²¹¹ At or ¹²⁵ I. In certain embodiments, X is At, preferably ²¹¹ At.

［式中、
Ｘは、Ｉ又はＡｔであり、
Ｒ_１は、上記定義されたとおりである］
で示されるものである。 In another embodiment of the reaction defined above, iodo-or astaarene is the formula (I-1) :.

[During the ceremony,
X is I or At,
R ₁ is as defined above]
It is indicated by.

In one embodiment, halogens are used in the diallyl iodonium compounds represented by the formulas (II), (II-1) and (II-2) and the iodine-or astatoarene represented by the formulas (I) and (I-1). Is represented by Cl, Br, I and At atoms. In one embodiment, the diallyl iodonium compounds represented by the formulas (II), (II-1) and (II-2) and the iodine- or astatoarene represented by the formulas (I) and (I-1) are fluorine. Does not contain atoms. In one embodiment, the diallyl iodonium compounds represented by the formulas (II) and (II-1) and the iodine- or astoarene represented by the formulas (I) and (I-1) contain two or more fluorine atoms. Not included.

In another embodiment of the reaction defined above, the iodide or astatinate salt is represented by formula (III) :.
A ⁺ X ^- (III)
[During the ceremony,
X is as defined above
A is a monovalent cation selected from Na, K, Cs, tetraalkylammonium and tetraalkylphosphonium]
It is indicated by.

In one embodiment of the reaction defined above, the reaction is in a solvent selected from the group consisting of alcohols such as acetonitrile, methanol, dimethylformamide, water and mixtures thereof, preferably a mixture of acetonitrile and water or a mixture thereof. Performed in acetonitrile. In one embodiment of the astatine labeling reaction defined above, the reaction is carried out in a solvent selected from the group consisting of methanol, water and mixtures thereof.

In one embodiment of the reaction defined above, this reaction is carried out in the presence of water. In one embodiment, the reaction is a base such NaOH, _{KOH, LiOH,} CsOH, carried out in the presence of _{K 2 CO 3, Na 2 CO} 3, Cs 2 CO 3 or a mixture thereof. Preferably, the base will be used if the diaryliodonium salt according to the invention does not contain a hydrolyzable functional group, such as an ester group.

In certain embodiments, for iodine labeling, acetonitrile or a mixture of acetonitrile and water is preferably at a temperature of 60 ° C to 140 ° C, preferably at a temperature of 90 ° C to 130 ° C, such as about 120 ° C. It is used as a solvent. In another particular embodiment, for astatine labeling, water, methanol, acetonitrile or mixtures thereof are used as the solvent, preferably at temperatures below 150 ° C., eg, at temperatures contained in 20-125 ° C. In one embodiment, for astatine labeling, the temperature is in the range of 40 ° C to 100 ° C.

In one embodiment of the reaction defined above, the water contained in the solvent is not evaporated. In one embodiment, the reaction is carried out in the presence of a catalyst, for example, Cu + or Cu 2 ⁺ salt.

In particular, Astatine labeling reaction, the ^{18 F} reaction In contrast, the presence of water, can be carried out at a low temperature (e.g. 40 ° C. to 100 ° C.). These conditions for the astatine labeling reaction yield high yields (eg, greater than 60%).

Purification Step In one embodiment, the method according to the present invention is a purification step in which iodine- or astathalene, preferably one represented by the formula (I) or (I-1), is extracted with a solvent. hand,
The astatate or iodide salt, preferably the one represented by the formula (III), and the diaryliodonium salt represented by the formula (II) or (II-1) are insoluble.
It comprises a purification step in which the iodine-or astathalene, preferably one represented by the formula (I) or (I-1), is soluble.

In one embodiment, the solvent is selected from diethyl ether; alkanes such as hexane, cyclohexane or heptane; mixtures of diethyl ether with alkanes; mixtures of alkanes with ethyl acetate; or mixtures of alkanes with ethyl acetate. It is preferably diethyl ether.

In another embodiment, the solvent is from diethyl ether; alkanes such as hexane, cyclohexane or heptane; toluene; a mixture of diethyl ether and alkanes; a mixture of alkanes and ethyl acetate; or a mixture of alkanes and ethyl acetate. It is selected, preferably diethyl ether.

In one embodiment, the purification step is repeated 1-5 times.

In one embodiment, the purification step is the following step:
i) Iodine-or astatine, preferably the corresponding diaryliodonium salt represented by formula (I) or (I-1), and optionally the corresponding diaryliodonium salt represented by formula (II) or (II-1). A step of evaporating and drying a solution containing an astatine or an iodine salt, preferably one represented by the formula (III), and ii) a step of adding diethyl ether.
iii) The step of evaporating and drying the iodine-or astaarene extracted with diethyl ether, and
including.

In one embodiment, in step iii), the extraction can be carried out with toluene.

In one embodiment, the methods defined above do not include purification steps by chromatography, such as high performance liquid chromatography (HPLC) or silica gel chromatography.

Steps for reducing astatine In one embodiment, the method defined above comprises the step of reducing astatine in advance. In one embodiment, the reduction is carried out in solution. The solvent can be acetonitrile; chloroform; alcohols such as methanol; dimethylformamide; water; and mixtures thereof; preferably water; mixtures of acetonitrile and water; or chloroform.

In certain embodiments, the reduction step is the following step:
i) The step of preparing the astatine solution with the above-defined solvent (ie, in the reduction step), preferably acetonitrile.
ii) This includes a step of obtaining a solution of an astatate salt by mixing the solution obtained in step i) with a solution containing a reducing agent, preferably an aqueous solution.

In another embodiment, the reduction step is the following step:
i) The step of preparing an astatine solution with the above-defined solvent, preferably chloroform, and
ii) A step of evaporating and drying the solution obtained in step i), preferably under N _{2 flow,}
iii) The present invention comprises a step of mixing the obtained dry residue of astatine with a solution containing a reducing agent, preferably an aqueous solution.

In one embodiment, the astatinated salt is the astatated salt represented by the above-defined formula (III).

In one embodiment, the reduction is _{a reducing agent selected from the group consisting of Na 2} SO ₃ , Na ₂ S ₂ O ₅ , Na ₂ S ₂ O _3, ascorbic acid salt, cysteine and hydrazine, preferably Na ₂ SO _3. Is done by.

In a particular embodiment, the method according to the invention comprises the following steps:
a) In the case of astatine labeling, the step of obtaining an astatine salt by reducing astatine, as defined above.
b) By reacting the diaryliodonium salt represented by the above-defined formula (II) or (II-1) with the astatate salt or iodide salt, the formula (I) or (I-1) is used, respectively. The process of obtaining the indicated iodide or astatine, and
c) The purification step defined above, wherein the iodo- or asteratoalane represented by the formula (I) or (I-1) is extracted with a solvent (the purification step is as defined above). And include.

In another particular embodiment, the method according to the invention is described in the following step:
a) In the case of astatine labeling, as defined above, by reducing astatine, the step of obtaining the astatine salt represented by the above-defined formula (III), and
b) By reacting the diaryliodonium salt represented by the above-defined formula (II) or (II-1) with the astatate salt or iodide salt represented by the above formula (III), respectively, the formula (I) Or the step of obtaining the iodine- or astatine as shown in (I-1), and
c) The purification step defined above, comprising the purification step of extracting iodine- or astoarene represented by the formula (I) or (I-1) with diethyl ether.

In one embodiment, in step c), extraction can be performed with toluene.

"Astatine-labeled" refers to the astathalene according to the present invention, particularly in the compounds represented by the formulas (I), (I-1) and (III), where X is At, particularly ^{211 At.} Means synthesis.

のうちの１つから選択され、一価のアニオンＹ⁻は、上記定義されたとおりであり、好ましくはＴｓＯ⁻又はＴｆＯ⁻である。 Diaryliodonium Represented by Formulas (II), (II-1) and (II-2) In another aspect, the present invention is a diaryliodonium salt represented by the above-defined formulas (II) and (II-1). Regarding itself. In particular, the diaryliodonium salt represented by the formula (II) is a specific compound described below:

The monovalent anion Y ⁻ selected from one of the above is as defined above, preferably TsO ⁻ or TfO ⁻ .

のうちの１つから選択される。 In particular, the diaryliodonium salt represented by the formula (II) is a specific compound described below:

It is selected from one of them.

のうちの１つから選択され、一価のアニオンＹ⁻は、上記定義されたとおりであり、好ましくはＢＦ４⁻、ＴｓＯ⁻又はＴｆＯ⁻である。 In particular, the diaryliodonium salt represented by the formula (II) is the following compound:

It is selected from one of the monovalent anion Y ^- is, are as defined above, preferably ^{BF4 @} -, TsO ^- or TfO ^- a.

［Ｘは、上記定義されたとおりであり、Ｒ_２は、エチニル、Ｎ_３及び−ＣＨ_２−Ｎ_３からなる群より選択される］
を有するヨード−及びアスタトアレーン化合物に関する。 Iodine and astaarene represented by the formulas (I), (I-1) and (I-3). Further, the present invention has the following formula (I-2):

[X is as defined above and R ₂ is selected from the group consisting of ethynyl, N ₃ and -CH _2- N _3].
Containing iodine-and asta-arene compounds having.

［Ｘは、上記定義されたとおりであり、Ｒ_ｐは、場合により置換されているテトラジン、（Ｃ_１〜Ｃ_６）アルキル又は−（Ｃ_１〜Ｃ_６）アルキレン−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキレン−Ｒｂであり、Ｒｑは、Ｈ又は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−Ｏ−（Ｃ_１〜Ｃ_６）アルキル、−Ｏ−（Ｃ_１〜Ｃ_６）アルケニル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルキレン−（Ｃ_６〜Ｃ_１０）アリールから選択される１つ又は複数の置換基により場合により置換されている（Ｃ_１〜Ｃ_６）アルキルである］
を有するヨード−及びアスタトアレーン化合物に関する。 Further, the present invention has the following formula (I-3):

[X is as defined above and R _p is optionally substituted tetrazine, (C _1- C ₆ ) alkyl or- _{(C 1- C 6} ) alkylene-N (Ra) -C ( O)-(C _{1 to} C ₆ ) alkylene-Rb, where Rq is H or N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl, Optionally substituted with one or more substituents selected from -O- (C _{1 to} C ₆ ) alkenyl and -O- (C _{1 to} C ₆ ) alkylene- (C _{6 to} C _{10) aryl.} (C _{1 to} C ₆ ) Alkyl]
Containing iodine-and asta-arene compounds having.

のうちの１つを有する、式（Ｉ）で示されるヨード−及びアスタトアレーン化合物に関する。 Further, the present invention has the following formula:

It relates to an iodine- and astatoarene compound represented by the formula (I) having one of the following.

Radiation Labeling Method The present invention is a method for synthesizing an iodine- or astato-labeled biomolecule and / or a vector.
(I) The step of synthesizing iodine-or astaarene according to the method defined above, and
(Ii) The present invention relates to a method comprising reacting the iodine-or astatharene with a biomolecule and / or a vector having a functional group reactive with the iodine-or astatoarene.

In one embodiment, the iodine-or astaarene is represented by the previously defined formula (I) or (I-1).

"The iodo or Application Store lanes with reactive functional groups" means an amino, thiol and bioorthoganol functional groups, for example N _3, alkynes and distortion alkenes. When a chemical reaction can be carried out in a complex biological medium without changing the medium, the chemical reaction is called "biological orthogonal type".

In one embodiment, in the radiolabeling method defined above, X is radioactive in the compounds represented by formulas (I) and (I-1). In one embodiment, X is selected from the group consisting of ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I and ^{211 At.} In certain embodiments, X is ²¹¹ At. In another particular embodiment, X is ¹²⁵ I.

Coupling methods are well known to those of skill in the art and can be found in the following literature:
David M. Wong and Shan S. Jameson, Chemistry of Protein and Nucleic Acid Cross-Linking and Conjugation Second Edition, CRC Press 2011 (NY), 604 p .;
NL Benoiton, Peptide Bond Formation: Active Esters in HoubenWeyl Methods of Organic Chemistry Synthesis of Peptides and Peptidomimetics (2001), WORKBENCH EDITION;
Emmanuel Basle, Nicolas Joubert and Mathieu Pucheault, Protein Chemical Modification on Endogenous Amino Acids, Chemistry & Biology (2010), Volume 17, Issue 3, 213-227;
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These methods are also known as conjugation methods, in which the compound represented by the formula (I) or (I-1) that binds to a vector and / or a biomolecule is referred to as a "conjugate".

The present invention relates to a conjugate comprising at least one iodo-or asta-arene according to the present invention, which is covalently attached to a vector or biomolecule via the functional group of the iodo-or asta-arene.

Finally, the present invention
With the diaryliodonium compound represented by the above-defined formula (II) or (II-1),
In some cases, with the reducing agents defined above,
In some cases, iodides or astatates salts, preferably those represented by formula (III) as defined above.
Optionally, relating to a radiolabeling kit comprising the biomolecules and / or vectors defined above.

［式中、
Ａｒ_１及びＡｒ_２は、それぞれ独立して、（Ｃ_６〜Ｃ_１０）アリール及びヘテロアリール基から選択され、前記アリール及びヘテロアリール基は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルキニル、場合により置換されているヘテロアリール、ハロゲン、ＮＯ_２、ＣＮ、Ｎ_３、ＣＦ_３、−ＯＲａ、−ＣＯＯＲｂ、−Ｃ（Ｏ）Ｒ_ａ、−Ｎ＝Ｃ＝Ｏ、−Ｎ＝Ｃ＝Ｓ、−Ｎ（Ｒａ）ＣＯＯＲｂ、−（Ｃ_１〜Ｃ_６）アルキル−Ｎ（Ｒａ）−Ｃ（Ｏ）−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキル−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキル−Ｒｂ、−（Ｃ_１〜Ｃ_６）アルキル−Ｎ（Ｒａ）−Ｃ（Ｏ）−（Ｃ_１〜Ｃ_６）アルキル−Ｃ（Ｏ）Ｏ−Ｒｂ及びマレイミドから選択される１つ又は複数の置換基により置換されており、
前記（Ｃ_１〜Ｃ_６）アルキル基は、Ｎ_３、ＯＨ、ＯＣＨ_３、ＣＦ_３、−Ｏ−ＣＨ_２−Ｏ−（Ｃ_１〜Ｃ_６）アルキル及び−Ｏ−（Ｃ_１〜Ｃ_６）アルケンから選択される１つ又は複数の置換基により場合により置換されており、
Ｒａは、Ｈ又は（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒｂは、Ｈ、（Ｃ_１〜Ｃ_６）アルキル並びにベクター及び／又は生体分子に結合可能な官能基からなる群より選択され、
Ｙは、一価のアニオンであり、特に、ＣＦ_３ＣＯＯ、ＴｓＯ、ＭｓＯ、ＮｓＯ、ＴｆＯ、ＮＯ_３、Ｂｒ、Ｃｌ、ＳＯ_４及びＢＦ_４から選択される］
で示されるものである、方法に関する。 The present invention also comprises reacting a diaryliodonium compound with an iodide or an astatine salt, respectively, to synthesize iodo- or astathalene, wherein the diaryliodonium compound is of formula (II) :.

[During the ceremony,
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl and (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) R _a , -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkyl-N (Ra) -C (O) -Rb,-(C _{1 to} C ₆ ) alkyl-N (Ra) -C ( O)-(C _{1 to} C ₆ ) alkyl-Rb,-(C _{1 to} C ₆ ) alkyl-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkyl-C (O) O-Rb And substituted with one or more substituents selected from maleimide,
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl and -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from the alkenes.
Ra is H or (C _1- C ₆ ) alkyl and is
Rb is, _H, is selected from the group consisting of _(C 1 _{~C 6)} alkyl and vectors and / or functional group capable of bonding to a biomolecule,
Y is a monovalent anion and is particularly selected from CF ₃ COO, TsO, MsO, NsO, TfO, NO ₃ , Br, Cl, SO ₄ and BF ₄ ].
With respect to the method, which is indicated by.

FIG. 1 shows the percentage of radiochemical yield (RCY) of the iodine labeling reaction, depending on the solvent and temperature used. FIG. 2 shows the percentage of radiochemical yield (RCY) of the astatine labeling reaction, depending on the solvent and temperature used.

Some examples are given below, but the present invention is not limited.

RCY means radiochemical yield.

ACN means acetonitrile.

Example 1: Synthesis of Diaryliodonium Salt Represented by Formula (II) Unless otherwise noted, all reagents and solvents were commercially obtained and used without further purification. ¹ H NMR and ¹³ C NMR spectra are recorded on a Bruker Advance 300 MHz instrument and chemical shifts are reported in ppm on the delta scale for TMS. Electrospray ionization-mass spectra (ESI-MS) were obtained using an Agilent LC / MSD system with multimode ions. Elemental analysis was performed by Galbraith Lab. Inc. (Knoxville, TN) using combustion analysis methods for C, H and N.

1. 1. General Method for Preparing Aryl-4-methoxyphenyliodonium Tosylate, A Compound Represented by Formula (II) 3-Chloroperbenzoic acid (1.77 mmol) dried in vacuum for 1 hour prior to use. Was _{dissolved in CHCl 3} (15 mL) and iodoaryl was added (1.5 mmol). The solution was stirred at rt for 15 minutes, turning slightly yellow and cloudy. Then, 4-toluenesulfonic acid hydrate (1.77 mmol) and anisole (8.05 mmol) were added, and the solution was heated at 40 ° C. for 2 hours and 30 minutes to turn bright yellow. The solvent was evaporated in vacuo and the oily residue was ground with _{Et 2 O until it turned into a solid.} The solid was redissolved in a minimal amount of MeOH and Et ₂ O was added until the solution became cloudy. This solution was placed in a refrigerator at 4 ° C. until iodonium tosylate settled or crystallized.

1.1. Phenyl (4-methoxyphenyl) iodonium tosylate White solid (47%). ¹ H NMR (CDCl ₃ , 300 MHz, ppm): δ 2.02 (s, 1H, broad), 2.30 (s, 3H), 3.78 (s, 3H), 6.83 (d, 2H, J = 9.0 Hz), 7.02 (d, 2H, J = 7.8 Hz), 7.29-7.34 (m, 2H), 7.44-7.52 (m, 3H), 7.85-7.92 (m, 4H). ¹³ C NMR (CDCl ₃ , 75 MHz, ppm): δ 21.5, 55.8, 104.1, 116.0, 117.7, 126.2, 128.7, 131.6, 131.8, 134.7, 137.6, 139.5. ESI-MS: m / z = 311.0 [M-OTs] ⁺ , 793.0 [2M-OTs] ⁺ . Mp: 154 ° C. C ₂₀ H ₁₉ IO ₄ S, calculated value: C, 49.80; H, 3.97. Measured value: C, 49.97; H, 3.88.

1.2. 4-Trill (4-Methoxyphenyl) iodonium tosylate Colorless crystals (77%). ¹ H NMR (CDCl ₃ , 300 MHz, ppm): δ 2.04 (s, 1H, broad), 2.31 (s, 3H), 2.33 (s, 3H), 3.78 (s, 3H), 6.81 (d, 2H, J = 9.3 Hz), 7.02 (d, 2H, J = 8.1 Hz), 7.11 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.1 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.85 (d, 2H, J = 9.3 Hz). ¹³ C NMR (CDCl ₃ , 75 MHz, ppm): δ 21.4, 21.5, 55.8, 104.1, 112.2, 117.6, 126.2, 128.6, 132.6, 134.7, 137.3, 139.4, 142.5, 143.0, 162.4. ESI-MS: m / z = 325.0 [M-OTs] ⁺ , 821.0 [2M-OTs] ⁺ . Mp: 169 ° C. C ₂₁ H ₂₁ IO ₄ S, calculated value: C, 50.82; H, 4.26. Measured value: C, 51.07; H, 4.03.

1.3. 3-Trill (4-Methoxyphenyl) iodonium tosylate Colorless crystals (69%). ¹ H NMR (CDCl ₃ , 300 MHz, ppm): δ 1.93 (s, 1H, broad), 2.29 (s, 3H), 2.31 (s, 3H), 3.79 (s, 3H), 6.84 (d, 2H, J = 9.3 Hz), 7.04 (d, 2H, J = 8.1 Hz), 7.18-7.29 (m, 2H), 7.54 (d, 2H, J = 8.1 Hz), 7.68 (d, 1H, J = 8.1 Hz) , 7.74 (s, 1H), 7.87 (d, 2H, J = 9.3 Hz). ¹³ C NMR (CDCl ₃ , 75 MHz, ppm): δ 21.4, 21.5, 55.8, 103.8, 115.7, 117.7, 126.2, 128.6, 131.5, 131.7, 132.6, 135.1, 137.5, 139.4, 142.4, 143.1, 162.5. ESI-MS: m / z = 325.0 [M-OTs] ⁺ , 821.0 [2M-OTs] ⁺ . Mp: 123 ° C. C ₂₁ H ₂₁ IO ₄ S, calculated value: C, 50.82; H, 4.26. Measured value: C, 50.89; H, 4.24.

1.4. 2-Trill (4-Methoxyphenyl) iodonium tosylate Colorless crystals (82%). ¹ H NMR (CDCl ₃ , 300 MHz, ppm): δ 2.17 (s, 1H, broad), 2.29 (s, 3H), 2.55 (s, 3H), 3.76 (s, 3H), 6.79 (d, 2H, J = 9.3 Hz), 6.99 (d, 2H, J = 8.1 Hz), 7.10-7.15 (m, 1H), 7.32 (d, 1H, J = 6.6 Hz), 7.39-7.46 (m, 3H), 7.79 ( d, 2H, J = 9 Hz), 8.1 (m, 1H). ¹³ C NMR (CDCl ₃ , 75 MHz, ppm): δ 21.5, 25.8, 55.7, 103.5, 117.5, 120.9, 126.1, 128.6, 129.2, 131.6, 132.7, 136.7, 137.5, 129.3, 141.3, 143.0, 162.2. ESI-MS: m / z = 325.0 [M-OTs] ⁺ , 821.0 [2M-OTs] ⁺ . Mp: 155 ° C. C ₂₁ H ₂₁ IO ₄ S, calculated value: C, 50.82; H, 4.26. Measured value: C, 50.90; H, 4.19.

1.5. 4-Chlorophenyl (4-methoxyphenyl) iodonium tosylate White solid (80%). ¹ H NMR (DMSO-d ₆ , 300 MHz, ppm): δ 2.29 (s, 3H), 3.80 (s, 3H), 7.06-7.12 (m, 4H), 7.47 (d, 2H, J = 7.8 Hz) , 7.59 (d, 2H, J = 8.4 Hz), 8.16-8.22 (m, 4H). ¹³ C NMR (DMSO-d ₆ , 75 MHz, ppm): δ 20.8, 55.7, 105.7, 114.9, 117.5, 125.5, 128.0, 131.6, 136.6, 137.1, 137.2, 137.6, 145.7, 162.0. ESI-MS: m / z = 344.9 / 346.9 [M-OTs] ⁺ , 860.9 / 862.9 [2M-OTs] ⁺ . Mp: 186 ° C. C ₂₀ H ₁₈ ClIO ₄ S, calculated value: C, 46.48; H, 3.51. Measured value: C, 46.54; H, 3.39.

1.6. 4- (ethoxycarbonyl) phenyl (4-methoxyphenyl) iodonium tosylate White solid (59%). ¹ H NMR (CDCl ₃ , 300 MHz, ppm): δ 1.36 (t, 3H, J = 7.0 Hz), 2.25 (s, 1H, broad), 2.29 (s, 3H), 3.77 (s, 3H), 4.35 (q, 2H, J = 7.0 Hz), 6.79 (d, 2H, J = 9.0 Hz), 6.97 (d, 2H, J = 7.8 Hz), 7.49 (d, 2H, J = 8.1 Hz), 7.84-7.92 (m, 4H), 7.99 (d, 2H, J = 8.1 Hz). ¹³ C NMR (CDCl ₃ , 75 MHz, ppm): δ 14.4, 21.4, 55.7, 61.8, 104.5, 117.6, 121.0, 126.1, 128.6, 132.1, 133.1, 134.8, 137.9, 139.5, 142.6, 162.5, 165.3. ESI-MS: m / z = 383.0 [M-OTs] ⁺ , 937.0 [2M-OTs] ⁺ . Mp: 137 ° C. C ₂₃ H ₂₃ IO ₆ S, calculated value: C, 49.83; H, 4.18. Measured value: C, 49.78; H, 4.14.

1.7. 4-Nitrophenyl (4-Methoxyphenyl) Iodonium Tosylate White solid (36%). ¹ H NMR (DMSO-d ₆ , 300 MHz, ppm): δ 2.29 (s, 3H), 3.80 (s, 3H), 7.08-7.11 (m, 4H), 7.47 (d, 2H, J = 8.1 Hz) , 8.22-8.30 (m, 4H), 8.42 (d, 2H, J = 8.7 Hz). ¹³ C NMR (DMSO-d ₆ , 75 MHz, ppm): δ 20.8, 55.8, 117.6, 117.6, 123.2, 125.5, 126.1, 128.0, 136.0, 137.6, 145.8, 149.2, 162.2. ESI-MS: m / z = 355.9 [M-OTs] ⁺ , 883.0 [2M-OTs] ⁺ . Mp: 192 ° C. C ₂₀ H ₁₈ INO ₆ S + 1 / 2H ₂ O, calculated value: C, 44.79; H, 3.57; N, 2.61. Measured value: C, 44.70; H, 3.18; N, 2.38.

1.8. 3-Nitrophenyl (4-Methoxyphenyl) iodonium tosylate White solid (35%). ¹ H NMR (DMSO-d ₆ , 300 MHz, ppm): δ 2.28 (s, 3H), 3.80 (s, 3H), 7.10 (m, 4H), 7.46 (d, 2H, J = 7.8 Hz), 7.79 (m, 1H), 8.26 (d, 2H, J = 8.7 Hz), 8.43 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 7.8 Hz), 9.12 (s, 1H). ¹³ C NMR (DMSO-d ₆ , 75 MHz, ppm): δ 20.8, 55.7, 105.9, 116.9, 117.6, 125.5, 126.5, 128.0, 129.5, 132.6, 137.5, 137.6, 140.8, 145.7, 148.2, 162.2. ESI-MS: m / z = 355.9 [M-OTs] ⁺ , 883.0 [2M-OTs] ⁺ . Mp: 174 ° C. C ₂₀ H ₁₈ INO ₆ S, calculated value: C, 45.55; H, 3.44; N, 2.66. Measured value: C, 45.53; H, 3.20; N, 2.37.

1.9. 4-Cyanophenyl (4-Methoxyphenyl) iodonium tosylate White solid (45%). ¹ H NMR (DMSO-d ₆ , 300 MHz, ppm): δ 2.29 (s, 3H), 3.80 (s, 3H), 7.10 (m, 4H), 7.47 (d, 2H, J = 7.8 Hz), 7.98 (d, 2H, J = 8.1 Hz), 8.21 (d, 2H, J = 8.7 Hz), 8.36 (d, 2H, J = 8.1 Hz). ¹³ C NMR (DMSO-d ₆ , 75 MHz, ppm): δ 20.7, 55.7, 105.5, 114.4, 117.5, 117.6, 121.1, 121.8, 125.5, 128.0, 134.8, 135.4, 137.5, 145.7, 162.3. ESI-MS: m / z = 336.0 [M-OTs] ⁺ , 842.9 [2M-OTs] ⁺ . Mp: 208 ° C. C ₂₁ H ₁₈ INO ₄ S + H ₂ O, calculated value: C, 48.01; H, 3.84; N, 2.67. Measured values: C, 47.90; H, 3.15; N, 2.34.

1.10. 4-Azidophenyl (4-Methoxyphenyl) iodonium tosylate White solid (60%). ¹ H NMR (400MHz, CD ₃ CN): 7.99-7.94 (m, 4H), 7.42 (d, 2H, 8 Hz), 7.09 (d, 2H, 8 Hz), 6.99 (d, 2H, 9.2 Hz), 6.95 (d, 2H, 9.2 Hz), 3.79 (s, 3H), 2.32 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): 163.8, 145.6, 145.5, 140.0, 138.3, 137.7, 129.4, 126.6, 123.20, 118.56, 110.3, 104.9, 56.6, 21.3. ESI-MS: m / z = 352.3 [M-OTs] ⁺ , 875.5 [2M-OTs] ⁺ .

1.11. 4-Azidomethylphenyl (4-Methoxyphenyl) iodonium tosylate White solid (74%). ¹ H NMR (400MHz, CD ₃ CN): 8.01-7.95 (m, 4H), 7.55 (d, 1H, 7.6 Hz), 7.46-7.43 (m, 3H), 7.09 (d, 2H, 8 Hz), 6.96 (d, 2H, 9.2 Hz), 4.40 (s, 2H), 3.80 (s, 3H), 2.31 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): 163.6, 145.3, 141.0, 140.1, 138.4, 135.2, 135.1, 132.8, 132.5, 129.3, 126.5, 118.4, 116.7, 104.5, 56.5, 53.9, 21.1. ESI-MS: m / z = 366.3 [M-OTs] ⁺ , 903.6 [2M-OTs] ⁺ .

1.12. 4-Ethynylphenyl (4-methoxyphenyl) iodonium tosylate White solid (64%). ¹ H NMR (400MHz, CD ₃ CN): 7.97-7.95 (m, 4H), 7.52-7.48 (m, 4H), 7.11 (d, 2H, 7.6 Hz), 7.05 (d, 2H, 8.8 Hz), 3.82 (s, 3H), 3.61 (s, 1H), 2.32 (s, 3H). ¹³ C NMR (100MHz, CD ₃ CN): 160.6, 142.0, 139.4, 136.2, 134.8, 132.3, 130.0, 128.2, 122.7, 120.3, 114.3, 111.9, 81.5, 80.7, 56.3, 19.9. ESI-MS: m / z = 335.3 [M-OTs] ⁺ , 841.5 [2M-OTs] ⁺ .

1.13. 3-N-Hydroxysuccinimidylphenyl ester (4-methoxyphenyl) Iodonium tosylate Beige solid (36%). ¹ H NMR (400MHz, CD ₃ CN): 2.31 (s, 3H), 2.86 (s, 4H), 3.81 (s, 3H), 6.98 (m, 2H), 7.09 (d, 2H, J = 7.6 Hz) , 7.42 (m, 2H), 7.61 (t, 1H, J = 8.0 Hz), 8.00 (m, 2H), 8.25 (m, 1H), 8.31 (m, 1H), 8.71 (m, 1H). ¹³ C NMR (100MHz, CD ₃ CN): 21.2, 26.4, 56.5, 104.5, 116.7, 118.6, 126.5, 128.7, 129.3, 133.3, 134.2, 137.0, 138.7, 140.1, 141.7, 145.2, 161.3, 163.9, 170.8. ESI-MS: m / z = 452.2 [M-OTs] ⁺ . About 5-10% hydrolyzed esters were also detected.

1.14. N-Hydroxysuccinimidylphenyl ester (4-methylethoxyphenyl) iodonium tosylate White crystals (39%). ¹ H NMR (CD3CN, 300 MHz, ppm): δ 1.29 (d, 6H, J = 6.0 Hz), 2.31 (s, 3H), 2.86 (s, 4H), 4.64 (m, 1H), 6.95 (m, 2H), 7.9 (d, 2H, J = 7.6 Hz), 7.44 (m, 2H), 7.62, t, 1H, J = 8.0 Hz), 7.97 (m, 2H), 8.27, m, 2H), 8.71 ( s, 1H). ¹³ C NMR (100MHz, CD ₃ CN): 15.6, 21.2, 21.9, 26.5, 71.7, 103.8, 116.7, 120.0, 126.5, 128.8, 129.4, 133.4, 134.3, 137.0, 138.9, 140.1, 141.7, 145.4, 161.3, 162.5 , 170.9. ESI-MS: m / z = 480.2 [M-OTs] ⁺ . About 10% hydrolyzed ester was also detected.

2. 2. Common methods for preparing iodonium triflate 3-chloroperbenzoic acid (504 μmol) dried in vacuum for 1 hour prior to use _{was dissolved in CH 2} Cl ₂ (5 mL) and iodoarene was added (5 mL). 458 μmol). After stirring for 15 minutes at room temperature, the desired arene (anisole, 1-methylethoxybenzene or thiophene, 504 μmol) was added, the solution was cooled to −20 ° C., and trifuric acid (916 μmol) was added. The resulting dark solution was stirred at −20 ° C. for 15 minutes. After returning to room temperature, the solvent was removed in vacuo and the residue was purified by flash chromatography using the appropriate gradient of _{CH 2} Cl _{2 and iPrOH.} The resulting purified iodonium triflate was then crystallized from _{CH 3} CN / Et _{2 O.} The compounds described in 2.1, 2.2, 2.3, 2.4 and 2.5 were obtained using this procedure.

2.1 3-N-Hydroxysuccini imidazole phenyl ester (4-methoxyphenyl) Iodium Triflate Obtained as white crystals from N-hydroxysuccini imidazole phenyl ester and anisole (28%). ¹ H NMR (CD3CN, 300 MHz, ppm): δ 2.86 (s, 4H), 3.85 (s, 3H), 7.08 (d, 2H, J = 6.9 Hz), 7.73 (t, 1H, J = 6.0 Hz) , 8.05 (d, 2H, J = 6.9 Hz), 3.22-8.36 (m, 2H), 8.75 (s, 1H). ¹³ C NMR (100MHz, CD ₃ CN): 26.5, 56.8, 102.2, 114.8, 119.3, 129.4, 134.0, 135.0, 137.0, 139.0, 141.7, 161.2, 164.6, 170.8. ESI-MS: m / z = 452.2 [M-OTf] ⁺ , 1053.0 [2M-OTf] ⁺ .

2.2 3-N-Hydroxysuccinimidylphenyl Ester (4-Methylethoxyphenyl) Iodium Triflate Obtained as white crystals from N-hydroxysuccinimidylphenyl ester and 1-methylethoxybenzene (36%). ¹ H NMR (CD3CN, 300 MHz, ppm): δ 1.96 (m, 6H), 2.88 (s, 4H), 4.70 (m, 1H), 7.05 (m, 2H), 7.74 (t, 1H, J = 8.0) Hz), 8.05 (m, 2H), 8.36 (m, 2H), 8.75 (s, 1H). ESI-MS: m / z = 480.3 [M-OTf] ⁺ .

2.3 3-N-Hydroxysuccini imidazole phenyl ester (2-thienyl) iodonium triflate N-hydroxysuccin imidazole phenyl ester and 1-methylethoxybenzene obtained as white crystals (17%). ¹ H NMR (CD3CN, 300 MHz, ppm): δ 2.88 (s, 4H), 7.24 (m, 1H), 7.76 (t, 1H, J = 8.0 Hz), 7.94 (m, 1H), 8.05 (m, 1H), 8.38 (m, 2H), 8.82, s, 1H). ESI-MS: m / z = 428.5 [M-OTf] ⁺ .

2.4 4-Methyl-2- [2,2,2-trifluoro-1-allyloxy-1- (trifluoromethyl) ethyl] phenyl- (4-methoxyphenyl) iodonium triflate Obtained as beige crystals ( 56%). ¹ H NMR (400MHz, CD ₃ CN): 2.44 (s, 3H), 3.95 (s, 3H), 4.94 (d, 2H, J = 6.0 Hz), 5.57 (d, 1H, J = 10,4 Hz) , 5.72 (d, 1H, J = 17.2 Hz), 6.17-6.27 (m, 1H), 7.09 (d, 1H, J = 8.6 Hz), 7.21 (d, 1H, J = 9.0 Hz), 7.37 (m, 1H), 7.73 (s, 1H), 8.03 (d, 1H, J = 9.0 Hz). ESI-MS: m / z = 517.3 [M-OTf] ⁺ .

2.5 4-Methyl-2- [2,2,2-trifluoro-1-methoxy-1- (trifluoromethyl) ethyl] phenyl- (4-methoxyphenyl) iodonium triflate Obtained as beige crystals (2,2-trifluoro-1-methoxy-1- (trifluoromethyl) ethyl). 53%). ¹ H NMR (400MHz, CD ₃ CN): 2.44 (s, 3H), 3.96 (s, 3H), 4.08 (s, 3H), 7.07 (d, 1H, J = 8.6 Hz), 7.23 (d, 2H, J = 9.2 Hz), 7.39 (d, 1H, J = 8.6 Hz), 7.72 (s, 1H), 8.07 (d, 2H, J = 9.2 Hz). ESI-MS: m / z = 491.2 [M-OTf] ⁺ .

2.6 4-Maleimidephenyl- (2-thienyl) iodonium triflate Obtained as colorless crystals (29%). ¹ H NMR (400MHz, CD ₃ CN): 6.98 (s, 2H), 7.23 (m, 1H), 7.58 (d, 2H, J = 7.2 Hz), 7.92 (d, 1H, J = 5.4 Hz), 8.02 (d, 1H, J = 5.4 Hz), 8.16 (d, 2H, J = 7.2 Hz). ESI-MS: m / z = 491.2 [M-OTf] ⁺ .

Example 2: Radiochemistry [ ^{125 I] NaI is commercially obtained from Perkin-Elmer (Shelton, CT) in a 10-5} M NaOH solution with a volumetric activity of 50 μCi / μL (1.85 MBq / μL) and used. Previously diluted with deionized water as desired. ^{The 209} Bi (α, 2n) ²¹¹ At reaction by irradiating a disposable internal bismuth target with alpha particles from the Cyclotron Corporation CS-30 cyclotron at the National Institutes of Health Positron Emission Tomography Department was used to generate ^{211 At.} Lindegren, S .; Back, T .; Jensen, HJ Appl Rad Isot 2001, 55, 157 was used to recover acetonitrile from irradiated targets at ^{211 At using the drying-distillation procedure.}

Prior to use, the ²¹¹ At solution was diluted twice with 10 mg / mL Na ₂ SO ₃ aqueous solution to give 1: 1 ACN / aqueous solution of Na At.

Alternatively, at the Arronax facility (St Herblain, France), the same nuclear reaction was used to ^{generate 211} At and dry distilled using the same procedure. In this case, ²¹¹ At was recovered in chloroform (CHCl ₃ ), and this solution was evaporated to dryness under a stream of nitrogen. The dried astatine was then redissolved in an appropriate volume of 1 mg / mL or 10 mg / mL aqueous sodium sulfite solution and then used for the astatine labeling reaction.

To 1.1 950Nmol iodonium salts equilibrated selected solvent 190μL reaction suitable reaction temperature of the iodonium salt and ¹²⁵ I, I was prepared from ^[125 I] NaI in commercial ¹⁰ -5 NaOH ^[125 I ] -NaI 10 μL (typically 1.5 MBq) was added and diluted with the appropriate amount of ultrapure water. At the desired time point, the aliquot was removed, placed on a silica gel TLC plate, eluted with the appropriate solvent and / or diluted to a water / ACN 1/1 mixture and analyzed by reverse phase HPLC using an appropriate elution system. .. The retention index and elution system used for all compounds in this study are given by ESI. Aromatic ¹²⁵ I was identified by comparison with cold analog retention indicators.

1.2 Reaction of iodonium salt with ²¹¹ At 20 μL (typically 5 MBq ^{) of [211} At] -NaAt prepared as above to 950 nmol iodonium salt in 180 μL of selective solvent equilibrated at the appropriate reaction temperature. ) Was added. At the desired time, the aliquot was removed, placed on a silica gel TLC plate, eluted with the appropriate solvent and / or diluted to a 0.1N HCl / ACN 1/1 mixture. ^The same elution system as in the 125I procedure was used. The retention index of the astatine-labeled compound was almost the same as its iodine-labeled analog.

Table 1: the ACN-5% asymmetric iodonium tosylate in _{H 2} O, RCY and selectivity for the target product of astatine labeled with radioiodinated reduction and 80 ° C. at 90 ° C. (30 min, n = 3 )

From these results, it is possible to obtain good yields for iodine-labeled reactions and high yields (> 70%) for astatine-labeled reactions, independent of the substituents present on the phenyl ring. Shown.

１mLのガラスバイアルに入れたＡＣＮ中の５mM ヨードニウム塩 ９５μLに、上記されたように調製された［^１２５Ｉ］ＮａＩ ５μL（５０〜５００μCi）を加えた。この溶液を９０℃で３０分間加熱した。室温に冷却した後、アリコートを取り出し、逆相ＨＰＬＣにより分析し、これから、８６％の放射化学収率（ＲＣＹ）を有する［^１２５Ｉ］−ＳＩＢの形成が示された。副生成物は、［^１２５Ｉ］−２−ヨードチオフェン（２％）、［^１２５Ｉ］−３−ヨード安息香酸（１．５％）及び約１０％ 未反応^１２５Ｉ⁻並びに分解生成物であった。 Example 3: Radiolabeled Biomolecule A-Iodine Labeled Biomolecule 1-Preparation of [ ¹²⁵ I] -SIB (N-succinimidyl 3-iodobenzoart) represented by formula (I)

To 95 μL of 5 mM iodonium salt in ACN in a 1 mL glass vial was added 5 μL (50-500 μCi) of ^{[125 I] NaI prepared as described above.} The solution was heated at 90 ° C. for 30 minutes. After cooling to room temperature, aliquots were removed and analyzed by reverse phase HPLC, which showed the formation of ^{[125 I] -SIB with an radiochemical yield (RCY) of 86%.} By-products were [ ¹²⁵ I] -2-iodothiophene (2%), [ ¹²⁵ I] -3-iodobenzoic acid (1.5%) and about 10% unreacted ¹²⁵ I- ^and degradation products. rice field.

Purification of [ ¹²⁵ I] -SIB was performed as follows:
The labeled mixture was dried under a stream of dry nitrogen to reduce the weight, and then _{100 μL of Et 2} O was added. The vial was vortexed for 30 seconds and transferred to the Et ₂ O to the vial of the two eyes of 1 mL. The Et ₂ O extraction procedure was repeated twice. Aliquots of the combined Et ₂ O layer was analyzed by HPLC, and now, that is 98% of pure ^[125 I] -SIB present, the remaining 2% correspond to ^[125 I] -3- iodobenzoic acid It was revealed. After drying weight loss under nitrogen flow, the [ ¹²⁵ I] -SIB can be readjusted to a suitable medium for conjugation to the selected biomolecule / vector.

In this extraction procedure, Et ₂ O can be replaced with toluene.

In addition, [ ¹²⁵ I] -SIB was produced from the following iodonium precursor using the same reaction conditions.

2- ^[125 I] Gets As conjugation above to -SIB of IgG 9E7.4, placed in a V- vial 1 mL, dried reduced in a stream of _{N 2} to ^[125 I] -SIB, DMSO ^20μL Was added. The solution was vortexed for 30 seconds and 100 μL of 5.65 mg / mL 9E7.4 IgG (anti-CD138) in 0.3 M borate buffer at pH 8.6 was added. After 30 minutes of stirring at 20 ° C., chromatograph controls using ITLC-SG strips and 10% TCA as eluent showed 75% conjugation yields. This solution was purified by gel filtration (PD10 column) using PBS as an eluent to give pure radiolabeled 9E7.4 IgG (radiochemical purity> 99%, as confirmed by ITLC-SG). ).

The same coupling reaction was performed on [ ²¹¹ At] -SAB with a conjugation yield of 75-88% (n = 3) and antibody immunoreactivity was conserved (85%).

3-Other radioactive iodine-labeled compounds represented by formula (I) obtained by the same procedure.

反応を１２０℃で３０分間行い、［^１２５Ｉ］−１−アジドメチル−４−ヨードベンゼン（８１％ ＲＣＹ）及び［^１２５Ｉ］−ヨードアニソール（６％）が形成された。

The reaction was carried out at 120 ° C. for 30 minutes to form [ ¹²⁵ I] -1-azidomethyl-4-iodobenzene (81% RCY) and [ ¹²⁵ I] -iodoanisole (6%).

反応を１２０℃で３０分間行い、［^１２５Ｉ］−１−アジド−４−ヨードベンゼン（５４％ ＲＣＹ）及び［^１２５Ｉ］−ヨードアニソール（５％）が形成された。

The reaction was carried out at 120 ° C. for 30 minutes to form [ ¹²⁵ I] -1-azido-4-iodobenzene (54% RCY) and [ ¹²⁵ I] -iodoanisole (5%).

反応を１２０℃で３０分間行い、［^１２５Ｉ］−１−エチニル−４−ヨードベンゼン（５４％ ＲＣＹ）及び［^１２５Ｉ］−ヨードアニソール（５％）が形成された。

The reaction was carried out at 120 ° C. for 30 minutes to form [ ¹²⁵ I] -1-ethynyl-4-iodobenzene (54% RCY) and [ ¹²⁵ I] -iodoanisole (5%).

上記されたように調製した後、［^１２５Ｉ］−１−アジドメチル−４−ヨードベンゼンの標識溶液を、副生成物である［^１２５Ｉ］−ヨードアニソールを溶媒と共に蒸発により除去することにより乾燥減量して、Ｅｔ_２Ｏ抽出物に分析的に純粋な［^１２５Ｉ］−１−アジドメチル−４−ヨードベンゼンサンプル（ＨＰＬＣ）がもたらされた。乾燥減量後、クリックトリペプチド １００μL（Ｈ_２Ｏ／ＡＣＮ（８：２）中の１．５mg/mL）を加え、バイアルを室温で３時間撹拌した。ＨＰＬＣ分析から、＞９９％のコンジュゲーション収率が示された。 Click-conjugation of 4- [ ¹²⁵ I] -1-azidomethyl-4-iodobenzene (81% RCY) with a model tripeptide

After prepared as above, ^{[125 I]} -1- azidomethyl-4-iodobenzene labeling solution, by-product ^{[125 I]} - loss on drying is removed by evaporation with solvent iodoanisole to, analytically pure to Et ₂ O extract ^[125 I] -1- azidomethyl-4-iodobenzene sample (HPLC) has resulted. After drying loss, click tripeptide 100 [mu] L: is added _{(H 2 O / ACN (8} 2) 1.5mg / mL in), the vial was stirred at room temperature for 3 hours. HPLC analysis showed a conjugation yield of> 99%.

アスタチン−２１１は、Arronax施設（St Herblain, France）により、クロロホルム溶液で提供された。使用前に、アスタチン−２１１を窒素流下でクロロホルムの蒸発乾固により、Ａｔ（−Ｉ）型に還元し、１mg/mL 亜硫酸ナトリウム溶液に再溶解した。ついで、１mLバイアルにおいて、Ｎａ^２１１Ａｔ ５μLを５mM濃度のＡＣＮ中のヨードニウム ９５μLに加えた。２５℃から１００℃への３０分間の加熱後、アリコートをＨＰＬＣにより分析した。 Preparation of B- ^{astatoarene 1- [211} At] -SAB (N-succinimidyl 3-astatobenzoart)

Astatine-111 was provided in chloroform solution by the Arronax facility (St Herblain, France). Prior to use, astatine-111 was reduced to At (-I) form by evaporative drying of chloroform under a stream of nitrogen and redissolved in 1 mg / mL sodium sulfite solution. Then, in a 1 mL vial, ^{5 μL of Na 211} At was added to 95 μL of iodonium in ACN at a 5 mM concentration. After heating from 25 ° C. to 100 ° C. for 30 minutes, the aliquots were analyzed by HPLC.

Use Et 2 _O, the same extraction procedure was utilized to radioiodinated of. For R = MeOPh, [ ²¹¹ At] -SAB was provided with 95% purity, 5% 4-astatoanisole.

In particular, the table above shows an unexpectedly ^{high reactivity of 211} At even at low temperatures (see, for example, for MeOPh, yield 91% at 40 ° C.). By comparison, ¹²⁵ I gives good yields above 80 ° C.

2-Other astatine-labeled compounds obtained by the same procedure

この反応を８０℃で３０分間行い、［^２１１Ａｔ］−１−アジドメチル−４−アスタトベンゼン（６５％ ＲＣＹ）及び［^２１１Ａｔ］−アスタトアニソール（１０％）が形成された。

This reaction was carried out at 80 ° C. for 30 minutes to form [ ²¹¹ At] -1-azidomethyl-4-astatobenzene (65% RCY) and [ ²¹¹ At] -astatoanisole (10%).

この反応を６０℃で３０分間行い、［^２１１Ａｔ］−１−アジド−４−アスタトベンゼン（４４％ ＲＣＹ）及び［^２１１Ａｔ］−アスタトアニソール（１７％）が形成された。

This reaction was carried out at 60 ° C. for 30 minutes to form [ ²¹¹ At] -1-azido-4-astatobenzene (44% RCY) and [ ²¹¹ At] -astatoanisole (17%).

この反応を１２０℃で３０分間行い、［^２１１Ａｔ］−１−エチニル−４−アスタトベンゼン（６６％ ＲＣＹ）及び［^２１１Ａｔ］−アスタトアニソール（１１％）が形成された。

This reaction was carried out at 120 ° C. for 30 minutes to form [ ²¹¹ At] -1-ethynyl-4-astatobenzene (66% RCY) and [ ²¹¹ At] -astatoanisole (11%).

Example 4: Comparison of Iodine Labeling and Astatine Labeling The results of studies on the effects of temperature and solvent are shown in FIGS. 1 and 2, showing a clearly distinguishable reactivity between iodide and astatine. Is done.

In the case of iodine labeling, the use of ACN results in high RCY above 100 ° C and up to 93% at 120 ° C.

In contrast, under all solvent conditions, more than 80% RCY was given below 100 ° C. for the astatine labeling reaction. This shows a strong difference in the reactivity between the two halogens. The reactivity of astatine could not be derived from the reactivity of iodine.

開始材料である３−（ｐ−ヨードフェニル）−６−メチル−１，２，４，５，テトラジンを以前に報告されたように調製した（Angewandte, 2012, 5222-52252）。アリールヨードニウム塩の調製を以前に報告された手順（Eur. J. Org. Chem. 2015, 5919-5924）から適応した。 Example 5:
Synthetic

The starting material 3- (p-iodophenyl) -6-methyl-1,2,4,5,tetrazine was prepared as previously reported (Angewandte, 2012, 5222-52252). The preparation of aryliodonium salts was adapted from the previously reported procedure (Eur. J. Org. Chem. 2015, 5919-5924).

TMSOAC (139 mg, 1.02 mmol) is added to a solution of Selectfluor® (177 mg, 470 μmol) in anhydrous acetonitrile (5 mL) under argon and the solution is kept at room temperature until the solution becomes clear (about 15). Minutes) Stirred. This solution was then added dropwise to a solution of 3- (p-iodophenyl) -6-methyl-1,2,4,5,tetrazine (101 mg, 340 μmol) dissolved in anhydrous acetonitrile (7.5 mL). .. The mixture was then stirred under argon at room temperature for 24 hours. Then, 4-methoxyphenyl trifluoroborate (84 mg, 370 μmol) and TMSOTFA (72 mg, 370 μmol) were added to this solution, and the solution was stirred under argon at room temperature for 4 days. Volatiles were removed by rotary evaporation and the crude product was purified by flash chromatography (SiO ₂ , CH ₂ Cl ₂ / methanol gradient) to give a purple solid (44 mg, 28%).
NMR ¹ H (CD ₃ CN, 400 MHz, ppm): δ 3.05 (s, 3H), 3.84 (s, 3H), 7.08 (d, 2H, J = 9.2 Hz), 8.06 (d, 2H, J = 9.2) Hz), 8.23 (d, 2H, J = 8.8 Hz), 8.59 (d, 2H, J = 8.8 Hz). NMR ¹³ C (CD ₃ CN, 100 MHz, ppm): 21.1, 56.4, 118.9, 131.4, 136.1, 136.9, 138.5, 163.5, 164.1, 168.8. NMR ¹⁹ F (CD ₃ CN): -152.2. ESI-MS: m / z = 405.3, [M-BF ₄ ] ⁺ .

−放射ヨウ素標識化：アリールヨードニウム塩（ＡＣＮ中の５mM） ９５μLに、Ｎａ^１２５Ｉ ５μLを加えた。この溶液を１００℃で１５分間加熱した。ＨＰＬＣ分析から、９６％の放射ヨウ素標識テトラジン及び２％の放射ヨウ素標識アニソールの形成が示された。粗溶液を蒸発乾固し、ＡｃＯＥｔ １００μLに溶解させ、順相シリカゲルカートリッジ（Sepak）において、ＡｃＯＥｔ ３００μLによる溶出により精製して、純粋な放射ヨウ素標識テトラジンを与えた（ＨＰＬＣにより＞９９％の放射化学純度）。 Radiation sign

-Radioiodine labeling: 95 μL of aryliodonium salt (5 mM in ACN) plus 5 μL of ^{Na 125 I.} The solution was heated at 100 ° C. for 15 minutes. HPLC analysis showed the formation of 96% radioactive iodine-labeled tetrazine and 2% radioactive iodine-labeled anisole. The crude solution was evaporated to dryness, dissolved in 100 μL AcOEt and purified by elution with 300 μL AcOEt in a normal phase silica gel cartridge (Sepak) to give pure radioactive iodine-labeled tetrazine (> 99% radiochemistry by HPLC). purity).

^{-Astatine labeling: Add 15 μL of Na 211} _{At (in 1 mg / mL Na 2} SO ₃ aqueous solution / MeOH 1: 2) to 85 μL of aryliodonium salt (3 mM in MeOH) and heat this solution at 40 ° C. for 30 minutes. bottom. HPLC analysis showed the formation of 91% astatine-labeled tetrazine and 9% astatine-labeled anisole. The crude solution was evaporated to dryness, dissolved in 100 μL of AcOEt and purified by elution with 300 μL of AcOEt in a normal phase silica gel cartridge (Sepak) to give pure astatine-labeled tetrazine (> 99% radiochemical purity by HPLC). ).

ＢＣＮ−ペプチド（９９：１ Ｈ_２Ｏ／ＭｅＯＨ中の１００μg/mL） ９０μLに、アスタチン標識テトラジン（ＭｅＯＨ中の１０μL）を加え、反応を逆相ＨＰＬＣによりモニタリングした。コンジュゲーション収率は、室温において、５分後に８５％及び１５分後に＞９９％であった。 Conjugation to Clickable Peptide Conjugation to BCN Peptide

BCN- Peptide: a ₍₉₉ 1 H 2 O / MeOH solution of 100 [mu] g / mL) 90 [mu] L, astatine labeled tetrazine a (10 [mu] L in MeOH) was added and the reaction was monitored by reverse phase HPLC. Conjugation yields were 85% after 5 minutes and> 99% after 15 minutes at room temperature.

ＴＣＯ−ペプチド（９９：１ Ｈ_２Ｏ／ＭｅＯＨ中の１００μg/mL） ９０μLに、アスタチン標識テトラジン（ＭｅＯＨ中の１０μL）を加え、反応を逆相ＨＰＬＣによりモニタリングした。コンジュゲーション収率は、室温において、１分後に９７％及び１５分後に＞９９％であった。 Conjugation to TCO-peptide

TCO- Peptide: a ₍₉₉ 1 H 2 O / MeOH solution of 100 [mu] g / mL) 90 [mu] L, astatine labeled tetrazine a (10 [mu] L in MeOH) was added and the reaction was monitored by reverse phase HPLC. Conjugation yields were 97% after 1 minute and> 99% after 15 minutes at room temperature.

ＣＨ_２Ｃｌ_２（６mL）中の開始材料であるヨウ化アリール（５００mg、１．０５mmol）に、ｍＣＰＢＡ（２６０mg、１．１６mmol）を加えた。この溶液を室温で３０分間撹拌した。ついで、アニソール（２２８mg、２．１１mmol）を加え、この溶液を−２０℃に冷却し、トリフリン酸を加えた（３１７mg、２．１１mmol）。−２０℃での４０分の撹拌後、この溶液をロータリーエバポレーションにより濃縮し、粗混合物をフラッシュクロマトグラフィー（ＳｉＯ_２、ＣＨＣｌ_３／ＭｅＯＨ勾配）により精製して、褐色の油状物を与えた。この油状物にジエチルエーテルを加え、室温での撹拌後、純粋なヨードニウム塩が沈殿する（６７mg、９％）。
NMR ¹H (CD₃CN, 400 MHz, ppm): δ 2.44 (s, 3H), 3.92 (s, 3H), 5.45 (s, 2H), 7.07 (d, 1H, J = 8.6 Hz), 7.15, (d, 2H, J = 9.2 Hz), 7.36, (d, 1 H, J = 8.6 Hz), 7.60-7.52 (m, 5H), 7.77 (s, 1H), 7.90 (d, 2H, J = 9.2 Hz)。ＥＳＩ−ＭＳ：ｍ／ｚ＝５８１．１、［Ｍ−ＴｆＯ］^＋。 Example 6
Synthetic

To _{the starting material in CH 2} Cl ₂ (6 mL), aryl iodide (500 mg, 1.05 mmol), mCPBA (260 mg, 1.16 mmol) was added. The solution was stirred at room temperature for 30 minutes. Anisole (228 mg, 2.11 mmol) was then added, the solution was cooled to −20 ° C. and trifuric acid was added (317 mg, 2.11 mmol). After 40 minutes of stirring at −20 ° C., the solution was concentrated by rotary evaporation and the crude mixture was purified by flash chromatography (SiO ₂ , CHCl ₃ / MeOH gradient) to give a brown oil. Diethyl ether is added to this oil, and after stirring at room temperature, a pure iodonium salt precipitates (67 mg, 9%).
NMR ¹ H (CD ₃ CN, 400 MHz, ppm): δ 2.44 (s, 3H), 3.92 (s, 3H), 5.45 (s, 2H), 7.07 (d, 1H, J = 8.6 Hz), 7.15, (d, 2H, J = 9.2 Hz), 7.36, (d, 1 H, J = 8.6 Hz), 7.60-7.52 (m, 5H), 7.77 (s, 1H), 7.90 (d, 2H, J = 9.2) Hz). ESI-MS: m / z = 581.1, [M-TfO] ⁺ .

工程１、求核置換：１mM アリールヨードニウム塩溶液（ＡＣＮ中の２８５μL）に、Ｎａ^２１１Ａｔ（１mg/mL Ｎａ_２ＳＯ_３溶液中の１５μL）を加える。この溶液を６０℃で１０分間加熱する。ＨＰＬＣ分析から、予測されたアスタチン標識種の形成が示され（＞９９％）、全くアスタトアニソールの痕跡は残らない。この溶液を窒素流下で蒸発させ、残留物をＣＨ_２Ｃｌ_２１００μLに溶解させ、Sepakシリカゲルカートリッジに載せる。ＣＨ_２Ｃｌ_２２００μLによる溶出により、純粋なアスタチン標識化合物が与えられる（ＨＰＬＣにより＞９９％の放射化学純度）。 Radiation sign

Step 1, Nucleophilic Substitution: To 1 mM aryliodonium salt solution (285 μL in ACN), add ^{Na 211} At (15 μL in 1 mg / mL Na ₂ SO _{3 solution).} The solution is heated at 60 ° C. for 10 minutes. HPLC analysis showed the predicted formation of astatine-labeled species (> 99%), leaving no trace of astatonisole. This solution is evaporated under a stream of nitrogen _{to dissolve the residue in 100 μL of CH 2} Cl ₂ and place it on a Sepak silica gel cartridge. Elution with 200 μL of CH ₂ Cl ₂ gives a pure astatine-labeled compound (> 99% radiochemical purity by HPLC).

Step 2, Deprotection: _{The purified astatine-labeled compound in CH 2} Cl ₂ solution was evaporated to dryness, 100 μL of TFA was added, and the mixture was stirred at room temperature for about 15 minutes. The TFA was evaporated with a stream of nitrogen. To remove trace amounts of residual TFA, _{100 μL of CH 3} CN was added and evaporated with a stream of nitrogen (repeated 3 times). HPLC analysis showed that 93% of the astatine-labeled species corresponding to the predicted deprotection product was formed.

Step 3, Hypervalent Astatine Formation: Dried deprotected astatine-labeled compound was dissolved in 100 μL of _{CCl 4.} Then 37% hydrochloric acid (2 μL) followed by NaOCl (2 μL) was added and the reaction was heated at 60 ° C. for 15 minutes. Aliquots were then analyzed by HPLC and this analysis showed conversion of the starting material to 90% hypervalent species. To further confirm the identity of the hypervalent species, the CCl ₄ solution was evaporated under _{N 2} flow and dissolved in 75 μL of _{CH 3 CN.} 20 μL of Na ₂ SO ₃ solution (100 mg / mL) was added and the solution was heated at 60 ° C. for 15 minutes. HPLC analysis of the aliquots of this solution showed that 75% of the first hypervalent species returned to the monovalent form.

ＣＨ_２Ｃｌ_２（３mL）中の開始材料であるヨウ化アリール（２９３mg、０．４５mmol）に、ｍＣＰＢＡ（１１１mg、０．４９mmol）を加えた。この溶液を室温で３０分間撹拌した。ついで、アニソール（９７mg、０．９mmol）を加え、この溶液を−２０℃に冷却し、トリフリン酸を加えた（１３５mg、０．９mmol）。−２０℃での１５分の撹拌後、この溶液をロータリーエバポレーションにより濃縮し、粗混合物をフラッシュクロマトグラフィー（ＳｉＯ_２、ＣＨ_２Ｃｌ_２／ＭｅＯＨ勾配）により精製して、褐色の油状物を与えた。ＡＣＮ／Ｅｔ_２Ｏ中での結晶化により、無色の結晶として当該化合物を提供した（１８mg、４％）。
NMR ¹H (CD₃CN, 400 MHz, ppm): δ 2.68 (t, 2H), 2.90 (s, 2H), 3.69 (t, 2H), 3.90 (s, 3H) 4.59 (s, 3H), 5.44 (s, 2H), 6.73 (s, 2H), 7.13 (m, 3H), 7.36 (m, 1H), 7.51 (m, 2H), 7.60 (m, 2H), 7.75 (s, 1H), 7.90 (m, 2H)。ＥＳＩ−ＭＳ：ｍ／ｚ＝７６０．９。 Example 7
Synthetic

To _{the starting material in CH 2} Cl ₂ (3 mL), aryl iodide (293 mg, 0.45 mmol), mCPBA (111 mg, 0.49 mmol) was added. The solution was stirred at room temperature for 30 minutes. Anisole (97 mg, 0.9 mmol) was then added, the solution was cooled to −20 ° C., and trifuric acid was added (135 mg, 0.9 mmol). After 15 minutes of stirring at -20 ° C, the solution is concentrated by rotary evaporation and the crude mixture is purified by flash chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH gradient) to give a brown oil. rice field. Crystallization in ACN / Et ₂ O in, to provide the compound as colorless crystals (18mg, 4%).
NMR ¹ H (CD ₃ CN, 400 MHz, ppm): δ 2.68 (t, 2H), 2.90 (s, 2H), 3.69 (t, 2H), 3.90 (s, 3H) 4.59 (s, 3H), 5.44 (s, 2H), 6.73 (s, 2H), 7.13 (m, 3H), 7.36 (m, 1H), 7.51 (m, 2H), 7.60 (m, 2H), 7.75 (s, 1H), 7.90 ( m, 2H). ESI-MS: m / z = 760.9.

工程１、求核置換：１mM アリールヨードニウム塩溶液（ＡＣＮ中の２８５μL）に、Ｎａ^２１１Ａｔ（１mg/mL Ｎａ_２ＳＯ_３溶液中の１５μL）を加える。この溶液を６０℃で１０分間加熱する。ＨＰＬＣ分析から、予測されたアスタチン標識種の形成が示され（＞９５％）、全くアスタトアニソールの痕跡は残らない。この溶液を窒素流下で蒸発させ、残留物をＣＨ_２Ｃｌ_２１００μLに溶解させ、Sepakシリカゲルカートリッジに載せる。ＣＨ_２Ｃｌ_２２００μLによる溶出により、純粋なアスタチン標識化合物が与えられる（ＨＰＬＣにより＞９９％の放射化学純度）。 Radiation sign

Step 1, Nucleophilic Substitution: To 1 mM aryliodonium salt solution (285 μL in ACN), add ^{Na 211} At (15 μL in 1 mg / mL Na ₂ SO _{3 solution).} The solution is heated at 60 ° C. for 10 minutes. HPLC analysis showed the predicted formation of astatine-labeled species (> 95%), leaving no trace of astatonisole. This solution is evaporated under a stream of nitrogen _{to dissolve the residue in 100 μL of CH 2} Cl ₂ and place it on a Sepak silica gel cartridge. Elution with 200 μL of CH ₂ Cl ₂ gives a pure astatine-labeled compound (> 99% radiochemical purity by HPLC).

Step 2, Deprotection: _{The purified astatine-labeled compound in CH 2} Cl ₂ solution was evaporated to dryness, 100 μL of TFA was added, and the mixture was stirred at 40 ° C. for about 15 minutes. The TFA was evaporated with a stream of nitrogen. To remove trace amounts of residual TFA, _{100 μL of CH 3} CN was added and evaporated with a stream of nitrogen (repeated 3 times). HPLC analysis showed that 92% of the astatine-labeled species corresponding to the predicted deprotection product was formed.

Step 3, Hypervalent Astatine Formation: Dried deprotected astatine-labeled compound was dissolved in 100 μL of _{CCl 4.} Then 37% hydrochloric acid (2 μL) followed by NaOCl (2 μL) was added and the reaction was heated at 60 ° C. for 30 minutes. Aliquots were then analyzed by HPLC and this analysis showed conversion of the starting material to 93% hypervalent species.

Claims (14)

A method for synthesizing astathalene comprising reacting a diallyl iodonium compound with an astatite salt, wherein the diaryliodonium compound is of formula (II) :.

[During the ceremony,
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl and (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) R _a , -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C ( O)-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-C (O) O-Rb And is substituted with one or more substituents selected from maleimidyl and
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl, and -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from alkenyl and -O- (C _1- C ₆ ) alkylene- (C _6- C _{10) aryl.}
Ra is H or (C _1- C ₆ ) alkyl and is
Rb is, _H, is selected from the group consisting of _(C 1 _{~C 6)} alkyl and vectors and / or functional group capable of bonding to a biomolecule,
Y is a monovalent anion]
The method, which is indicated by. Equation (II):

In the diallyl iodonium compound represented by
Ar ₁ and Ar ₂ are independently _{selected from (C 6 to} C ₁₀ ) aryl and heteroaryl groups, and the aryl and heteroaryl groups are (C _{1 to} C ₆ ) alkyl, (C _{2 to} C). ₆ ) Alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb , - (C 1 ~C 6) alkylene -N (Ra) -C (O) -Rb, - (C 1 ~C 6) alkylene -N (Ra) -C (O )-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-C (O) O-Rb and It has been substituted with one or more substituents selected from maleimidyl and has been substituted.
The (C _{1 to} C ₆ ) alkyl groups are N ₃ , OH, OCH ₃ , CF ₃ , -O-CH _2- O- (C _{1 to} C ₆ ) alkyl, -O- (C _{1 to} C ₆ ). It is optionally substituted with one or more substituents selected from alkenyl and -O- (C _1- C ₆ ) alkylene- (C _6- C _{10) aryl.}
Ra is H or (C _{1 to} C ₆ ) alkyl,
Rb consists of H, (C _1- C ₆ ) alkyl, succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, cyclooctynyl, norbornenyl, cyclopropenyl, bicyclononinyl and trans-cyclooctenyl. Selected from the group,
The method of claim 1, wherein Y is a monovalent anion. The diallyl iodonium compound is of formula (II-1) :.

[During the ceremony,
R ₁ is (C _{1 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkynyl, optionally substituted heteroaryl, halogen, NO ₂ , CN, N ₃ , CF ₃ , -ORa, -COORb, -C (O) Ra, -N = C = O, -N = C = S, -N (Ra) COORb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Rb _, -(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O)-(C _{1 to} C ₆ ) alkylene-Rb,-(C _{1 to} C ₆ ) alkylene-N (Ra) -C (O) -Selected from the group consisting of (C _1- C ₆ ) alkylene-C (O) O-Rb and maleemidyl.
The (C _1- C ₆ ) alkyl groups are optionally substituted with one or more substituents selected from _{N 3} , OH, OCH ₃ , CF ₃ and -O-CH ₂ -CH = CH _2. Ori,
Ra and Rb are as defined in claim 1.]
The method according to claim 1, which is shown in 1. Astatoarene has the formula (I):
Ar-X (I)
[During the ceremony,
X is At,
Ar is Ar ₁ or Ar ₂ ]
The method according to claim 1 or 2, which is shown in 1. The astatate salt is the formula (III):
A ⁺ X ^- (III)
[During the ceremony,
X is as defined in claim 4.
A is a monovalent cation selected from Na, K, Cs, tetraalkylammonium and tetraalkylphosphonium]
The method according to any one of claims 1 to 4, which is shown in 1. The method of claim 4 or 5, wherein X is radioactive. The method according to claim 6, wherein X is ^{211 At.} The method according to any one of claims 1 to 7, wherein the reaction is carried out in a solvent selected from the group consisting of alcohols such as acetonitrile and methanol, dimethylformamide, water and mixtures thereof. Further, it is a purification step of extracting astathalene with a solvent.
The astatate salt and the diallyl iodonium salt represented by the formula (II) are insoluble and are insoluble.
The method according to any one of claims 1 to 8, comprising a purification step in which the astatharene is soluble. The method for synthesizing astathalene according to any one of claims 1 to 9, which comprises a step of reducing astatine in advance. A method of synthesizing an ast-labeled biomolecule and / or vector.
(I) A step of synthesizing astatharene according to the method according to any one of claims 1 to 10.
(Ii) A method comprising a step of reacting the astathalene with a biomolecule and / or a vector having a functional group reactive with the astatoarene. The following formula:

Asta Alane, which has one of them. The following formula:

A diallyl iodonium salt having one of them. The method according to claim 1 or 2, wherein Y in the formula (II) is _{selected from the group consisting of CF 3} COO, TsO, MsO, NsO, TfO, NO ₃ , Br, Cl, SO ₄ and BF _4.

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